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- Social cognition impairment in genetic frontotemporal dementia within the GENFI cohortPublication . Russell, Lucy L.; Greaves, Caroline V.; Bocchetta, Martina; Nicholas, Jennifer; Convery, Rhian S.; Moore, Katrina; Cash, David M.; van Swieten, John; Jiskoot, Lize; Moreno, Fermin; Sanchez-Valle, Raquel; Borroni, Barbara; Laforce, Robert; Masellis, Mario; Tartaglia, Maria Carmela; Graff, Caroline; Rotondo, Emanuela; Galimberti, Daniela; Rowe, James B.; Finger, Elizabeth; Synofzik, Matthis; Vandenberghe, Rik; de Mendonça, Alexandre; Tagliavini, Fabrizio; Santana, Isabel; Ducharme, Simon; Butler, Chris; Gerhard, Alex; Levin, Johannes; Danek, Adrian; Otto, Markus; Warren, Jason D.; Rohrer, Jonathan D.; Rossor, Martin N.; Fox, Nick C.; Woollacott, Ione O.C.; Shafei, Rachelle; Heller, Carolin; Guerreiro, Rita; Bras, Jose; Thomas, David L.; Mead, Simon; Meeter, Lieke; Panman, Jessica; Papma, Janne; Poos, Jackie; van Minkelen, Rick; Pijnenburg, Yolanda; Barandiaran, Myriam; Indakoetxea, Begoña; Gabilondo, Alazne; Tainta, Mikel; de Arriba, Maria; Gorostidi, Ana; Zulaica, Miren; Villanua, Jorge; Diaz, Zigor; Borrego-Ecija, Sergi; Olives, Jaume; Lladó, Albert; Balasa, Mircea; Antonell, Anna; Bargallo, Nuria; Premi, Enrico; Cosseddu MPsych, Maura; Gazzina, Stefano; Padovani, Alessandro; Gasparotti, Roberto; Archetti, Silvana; Black, Sandra; Mitchell, Sara; Rogaeva, Ekaterina; Freedman, Morris; Keren, Ron; Tang-Wai, Daid; Öijerstedt, Linn; Andersson, Christin; Jelic, Vesna; Thonberg, Hakan; Arighi, Andrea; Fenoglio, Chiara; Scarpini, Elio; Fumagalli, Giorgio; Cope, Thomas; Timberlake, Carolyn; Rittman, Timothy; Shoesmith, Christen; Bartha, Robart; Rademakers, Rosa; Wilke, Carlo; Karnarth, Hans-Otto; Bender, Benjamin; Bruffaerts, Rose; Vandamme, Philip; Vandenbulcke, Mathieu; Ferreira, Catarina B.; Miltenberger, Gabriel; Maruta MPsych, Carolina; Verdelho, Ana; Afonso, Sónia; Taipa, Ricardo; Caroppo, Paola; Di Fede, Giuseppe; Giaccone, Giorgio; Muscio, Cristina; Prioni, Sara; Redaelli, Veronica; Rossi, Giacomina; Tiraboschi, Pietro; Duro NPsych, Diana; Almeida, Maria R.; Castelo-Branco, Miguel; Leitão, Maria J.; Tabuas-Pereira, Miguel; Santiago, Beatriz; Gauthier, Serge; Rosa-Neto, Pedro; Veldsman, Michele; Thompson, Paul; Langheinrich, Tobias; Prix, Catharina; Hoegen, Tobias; Wlasich, Elisabeth; Loosli, Sandra; Schonecker, Sonja; Semler, Elisa; Anderl-Straub, SarahA key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease.
- Differential early subcortical involvement in genetic FTD within the GENFI cohortPublication . Bocchetta, Martina; Todd, Emily G.; Peakman, Georgia; Cash, David M.; Convery, Rhian S.; Russell, Lucy L.; Thomas, David L.; Eugenio Iglesias, Juan; van Swieten, John C.; Jiskoot, Lize C.; Seelaar, Harro; Borroni, Barbara; Galimberti, Daniela; Sanchez-Valle, Raquel; Laforce, Robert; Moreno, Fermin; Synofzik, Matthis; Graff, Caroline; Masellis, Mario; Carmela Tartaglia, Maria; Rowe, James B.; Vandenberghe, Rik; Finger, Elizabeth; Tagliavini, Fabrizio; de Mendonça, Alexandre; Santana, Isabel; Butler, Chris R.; Ducharme, Simon; Gerhard, Alexander; Danek, Adrian; Levin, Johannes; Otto, Markus; Sorbi, Sandro; Le Ber, Isabelle; Pasquier, Florence; Rohrer, Jonathan D.; Afonso, Sónia; Rosario Almeida, Maria; Anderl-Straub, Sarah; Andersson, Christin; Antonell, Anna; Archetti, Silvana; Arighi, Andrea; Balasa, Mircea; Barandiaran, Myriam; Bargalló, Nuria; Bartha, Robart; Bender, Benjamin; Benussi, Alberto; Bertoux, Maxime; Bertrand, Anne; Bessi, Valentina; Black, Sandra; Borrego-Ecija, Sergi; Bras, Jose; Brice, Alexis; Bruffaerts, Rose; Camuzat, Agnès; Cañada, Marta; Cantoni, Valentina; Caroppo, Paola; Castelo-Branco, Miguel; Colliot, Olivier; Cope, Thomas; Deramecourt, Vincent; de Arriba, María; Di Fede, Giuseppe; Díez, Alina; Duro, Diana; Fenoglio, Chiara; Ferrari, Camilla; Ferreira, Catarina B.; Fox, Nick; Freedman, Morris; Fumagalli, Giorgio; Funkiewiez, Aurélie; Gabilondo, Alazne; Gasparotti, Roberto; Gauthier, Serge; Gazzina, Stefano; Giaccone, Giorgio; Gorostidi, Ana; Greaves, Caroline; Guerreiro, Rita; Heller, Carolin; Hoegen, Tobias; Indakoetxea, Begoña; Jelic, Vesna; Karnath, Hans-Otto; Keren, Ron; Kuchcinski, Gregory; Langheinrich, Tobias; Lebouvier, Thibaud; João Leitão, Maria; Lladó, Albert; Lombardi, Gemma; Loosli, Sandra; Maruta, Carolina; Mead, Simon; Meeter, Lieke; Miltenberger, Gabriel; van Minkelen, Rick; Mitchell, Sara; Moore, Katrina; Nacmias, Benedetta; Nelson, Annabel; Nicholas, Jennifer; Öijerstedt, Linn; Olives, Jaume; Ourselin, Sebastien; Padovani, Alessandro; Panman, Jessica; Papma, Janne M.; Pijnenburg, Yolande; Polito, Cristina; Premi, Enrico; Prioni, Sara; Prix, Catharina; Rademakers, Rosa; Redaelli, Veronica; Rinaldi, Daisy; Rittman, Tim; Rogaeva, Ekaterina; Rollin, Adeline; Rosa-Neto, Pedro; Rossi, Giacomina; Rossor, Martin; Santiago, Beatriz; Saracino, Dario; Sayah, Sabrina; Scarpini, Elio; Schönecker, Sonja; Semler, Elisa; Shafei, Rachelle; Shoesmith, Christen; Swift, Imogen; Tábuas-Pereira, Miguel; Tainta, Mikel; Taipa, Ricardo; Tang-Wai, David; Thompson, Paul; Thonberg, Hakan; Timberlake, Carolyn; Tiraboschi, Pietro; Van Damme, Philip; Vandenbulcke, Mathieu; Veldsman, Michele; Verdelho, Ana; Villanua, Jorge; Warren, Jason; Wilke, Carlo; Woollacott, Ione; Wlasich, Elisabeth; Zetterberg, Henrik; Zulaica, MirenBackground: Studies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups. Methods: 480 mutation carriers from the Genetic FTD Initiative (GENFI) were included (198 GRN, 202 C9orf72, 80 MAPT), together with 298 non-carrier cognitively normal controls. Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans. Mutation carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score: asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more). Results: In all three groups, subcortical involvement was seen at the CDR 0.5 stage prior to phenoconversion, whereas in the C9orf72 and MAPT mutation carriers there was also involvement at the CDR 0 stage. In the C9orf72 expansion carriers the earliest volume changes were in thalamic subnuclei (particularly pulvinar and lateral geniculate, 9-10%) cerebellum (lobules VIIa-Crus II and VIIIb, 2-3%), hippocampus (particularly presubiculum and CA1, 2-3%), amygdala (all subregions, 2-6%) and hypothalamus (superior tuberal region, 1%). In MAPT mutation carriers changes were seen at CDR 0 in the hippocampus (subiculum, presubiculum and tail, 3-4%) and amygdala (accessory basal and superficial nuclei, 2-4%). GRN mutation carriers showed subcortical differences at CDR 0.5 in the presubiculum of the hippocampus (8%). Conclusions: C9orf72 expansion carriers show the earliest and most widespread changes including the thalamus, basal ganglia and medial temporal lobe. By investigating individual subregions, changes can also be seen at CDR 0 in MAPT mutation carriers within the limbic system. Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms.
- Disease-related cortical thinning in presymptomatic granulin mutation carriersPublication . Borrego-Écija, Sergi; Sala-Llonch, Roser; van Swieten, John; Borroni, Barbara; Moreno, Fermín; Masellis, Mario; Tartaglia, Carmela; Graff, Caroline; Galimberti, Daniela; Laforce, Robert; Rowe, James B; Finger, Elizabeth; Vandenberghe, Rik; Tagliavini, Fabrizio; de Mendonça, Alexandre; Santana, Isabel; Synofzik, Matthis; Ducharme, Simon; Levin, Johannes; Danek, Adrian; Gerhard, Alex; Otto, Markus; Butler, Chris; Frisoni, Giovanni; Sorbi, Sandro; Heller, Carolin; Bocchetta, Martina; Cash, David M; Convery, Rhian S; Moore, Katrina M; Rohrer, Jonathan D; Sanchez-Valle, Raquel; Rossor, Martin N.; Fox, Nick C.; Woollacott, Ione O.C.; Shafei, Rachelle; Greaves, Caroline; Neason, Mollie; Guerreiro, Rita; Bras, Jose; Thomas, David L.; Nicholas, Jennifer; Mead, Simon; Meeter, Lieke; Panman, Jessica; Papma, Janne; van Minkelen, Rick; Pijnenburg, Yolande; Indakoetxea, Begoña; Gabilondo, Alazne; TaintaMD, Mikel; de Arriba, Maria; Gorostidi, Ana; Zulaica, Miren; Villanua, Jorge; Diaz, Zigor; Olives, Jaume; Lladó, Albert; Balasa, Mircea; Antonell, Anna; Bargallo, Nuria; Premi, Enrico; Cosseddu, Maura; Gazzina, Stefano; Padovani, Alessandro; Gasparotti, Roberto; Archetti, Silvana; Black, Sandra; Mitchell, Sara; Rogaeva, Ekaterina; Freedman, Morris; Keren, Ron; Tang-Wai, David; Öijerstedt, Linn; Andersson, Christin; Jelic, Vesna; Thonberg, Hakan; Arighi, Andrea; Fenoglio, Chiara; Scarpini MD, Elio; Fumagalli, Giorgio; Cope, Thomas; Timberlake, Carolyn; Rittman, Timothy; Shoesmith, Christen; Bartha, Robart; Rademakers, Rosa; Wilke, Carlo; Bender, Benjamin; Bruffaerts, Rose; Vandamme, Philip; Vandenbulcke, Mathieu; Maruta, Carolina; Ferreira, Catarina B.; Miltenberger, Gabriel; Verdelho, Ana; Afonso, Sónia; Taipa, Ricardo; Caroppo, Paola; Di Fede, Giuseppe; Giaccone, Giorgio; Prioni, Sara; Redaelli, Veronica; Rossi, Giacomina; Tiraboschi, Pietro; Duro, Diana; Rosario Almeida, Maria; Castelo-Branco, Miguel; João Leitão, Maria; Tabuas-Pereira, Miguel; Santiago, Beatriz; Gauthier, Serge; Rosa-Neto, Pedro; Veldsman, Michele; Flanagan, Toby; Prix, Catharina; Hoegen, Tobias; Wlasich, Elisabeth; Loosli, Sandra; Schonecker, Sonja; Semler, Elisa; Anderl-Straub, SarahMutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.